Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/02—Preparation
  • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents

Definitions

• the present invention relates to a method for producing a novel cephalosporin derivative and a salt thereof.
• R 2 is as defined above
• the present inventors have conducted various studies on the improved production method of the novel cephalosporin derivative (I) and a salt thereof, and found that the cephalosporin derivative (I) and the cephalosporin derivative (I) were efficiently produced by the following method. We found that this salt was obtained, and completed Honkiaki.
• the present study provides a method for producing a cephalosporin derivative (I) and a salt thereof.
• the present invention also provides an intermediate (ie, the compound (V) described below) for producing the cephalosvon derivative (I) and a salt thereof, and a method for producing the same.
• cephalosporin derivative (I) of the present invention and a salt thereof are produced as follows.
• the compound (II) is used in the present reaction as free carboxylic acid or as an alkali metal salt thereof or a reactive derivative thereof. That is, as free acid, or as sodium, potassium, Calcium, Triethylamine, Bi! / As a salt such as pyridine or a reactive derivative thereof, for example, acid halides (acid chlorides, acid bromides, etc.), acid anhydrides, mixed acid anhydrides [substituted phosphoric acid (dialkyl lin Acids, etc.), alkyl carbonates (eg, monoethyl carbonate), etc .: Activated amides (amides with imidazole, etc.), esters (cyanomethyl esters, 412-nitrophenol esters, etc.) Then, it is subjected to the acylation reaction.
• acid halides acid chlorides, acid bromides, etc.
• acid anhydrides mixed acid anhydrides
• substituted phosphoric acid dialkyl lin Acids, etc.
• the compound (m) is used as it is as a free carboxylic acid, it is preferable to use an appropriate condensing agent.
• N, N' such as dicyclohexylcarbodiimide; di-substituted carbodiimides, N, N, -Carbonyldimidazole,, N'-Thionyldiimidazole, azolide
• a dehydrating agent such as a compound is used. When these condensing agents are used, the reaction is thought to proceed via a reactive derivative of the carboxylic acid. This reaction is usually performed in an inert solvent.
• solvent Physically, water, aceton, dioxane, acetonitrile, black mouth form, benzene, methylene chloride, salt water ethylene, tetrahedral water And organic solvents such as ethyl acetate, N, N-dimethylformamide and pyridine, and mixtures thereof.
• This reaction is preferably carried out at about 20 t: t35.
• R 1 is formyl, t—butoxycarbonyl, 1—methylone 2 —methoxy nicolepo 'twonoreh' twonorth, 1-methinole 2 -ethoxycarbonyl
• a method for producing a compound represented by the formula (1) by subjecting the compound to an amino-protecting group is a method for producing a compound represented by the formula (1) by subjecting the compound to an amino-protecting group.
• Separation reactions include, for example, conventional methods such as hydrolysis and reduction. Law.
• the hydrolysis is desirably performed in the presence of an acid.
• the acid examples include an inorganic acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), an organic acid (for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, methansnorephonic acid, benzenesnolephonic acid, p — Tonolenesulfonate), acidic ion-exchange resins and the like.
• an organic acid such as trifluoro pi-acetic acid or ⁇ -triene sulfonic acid
• the reaction may be performed in the presence of a cation scavenger (for example, anisol). Desirable.
• Hydrolysis usually does not adversely affect the reaction, such as conventional solvents such as water, methanol, ethanol, ethanol, tert-butyl alcohol, tert-butyl alcohol, tetrahydrofuran.
• solvents such as water, methanol, ethanol, ethanol, tert-butyl alcohol, tert-butyl alcohol, tetrahydrofuran.
• the reaction temperature of this hydrolysis is not particularly limited.
• Reduction is performed by a conventional method such as chemical reduction or catalytic reduction.
• Suitable reducing agents used for chemical reduction include metals (eg, tin, zinc, iron, etc.) or metal compounds (eg, chromium chloride, chromium acetate, etc.) and organic or inorganic acids (f Acid, acetic acid, brobionic acid, trifluoroacetic acid, P-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
• a suitable catalyst used for catalytic reduction is a conventional catalyst,
• platinum sensitive media eg, platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
• palladium catalyst eg, palladium sponge, no, 'radium black, palladium oxide, palladium oxide
• carbon cobalt, barium, radium 'barium group oxide, ha' radium ⁇ barium carbonate, etc.
• nickel catalysts eg, reduced nickel, nickel oxide, Raney nickel, etc.
• Cobalt catalysts for example, reduced cobalt, Raney-cobalt, etc.
• iron catalysts for example, reduced iron, Raney and iron, etc.
• steel catalysts for example, reduced copper, Raney-copper, Uruman copper, etc.
• the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction, for example, water, methanol, ethanol, pronodium, N, N-dimethylformamide or a mixture thereof.
• a solvent which does not adversely influence the reaction
• the acid used for the chemical reduction is a liquid, these can be used as a solvent.
• suitable solvents used for the tangible reduction include the above-mentioned solvents. Solvents such as ether, dioxane, tetrahydrofuran or mixtures thereof can also be used.
• the reaction temperature for this reduction is not particularly limited.
• the elimination method described above is appropriately selected depending on the type of the protecting group to be separated. .
• Compound (V) is a novel compound and is produced, for example, as follows.
• Acid anhydrides Acid anhydrides, mixed acid anhydrides (substituted phosphoric acid (dialkyl)
• alkyl carbonic acid (mono-diethyl carbonate, etc.), etc.
• V / 1PO For example, carbodimids, and hydrating agents such as azolide compounds such as N'-carbonyldimidazole and N, N, thionyldimidazole are used. When these condensing agents are used, the reaction is thought to proceed via a reactive derivative of carboxylic acid. This reaction is usually performed in an inert solvent. Examples of the solvent include water, aceton, dioxane, acetonitrile, macropore form, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, -dimethyl Organic solvents such as tilformamide and pyridine, and mixtures thereof.
• the solvent include water, aceton, dioxane, acetonitrile, macropore form, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, -d
• the reaction is usually carried out at a temperature of ⁇ 30-C to 50′c, preferably at ⁇ 20 to ⁇ 20.
• R 3 is hydrogen or an amino-protecting group.
• X represents a group a reactive with the ⁇ - carboxyl group (the reactive group).
• R 3 in the general formula () as the protecting group for the amino group, Protecting groups for amino groups known per se, for example benzylcarbonyl, 2-phenyl-2-acetyl, 2-furinoleacetyl, D-5-amino-5-butanol, trityl, phthalimi , Holmil, t-butoxycreponyl, 1-methyl-2- methoxycarbonyl, 1.-methyl-2-ethoxycarbonyl, and so on.
• the “reactive group with the carboxyl group (the reactive group) represented by X” includes, for example, halogen (bromide, chloronole, and chloride), acrexles ruphonyloxy (meth Tansolephonyloxy), arylenosulfonyloxy (p-toluenesulfonyloxy, etc.), and hydroxy.
• Compound () is used in the present reaction as free carboxylic acid or as a reactive derivative thereof. That is, it is subjected to the acylation reaction as a reactive derivative similar to the reactive derivative relating to the free acid or the compound (VI).
• an appropriate condensing agent can be used.
• the same condensing agent as described above is used.
• the reaction is thought to proceed via a reactive derivative of rubonic acid.
• This reaction is usually carried out at a temperature of ⁇ 30 ⁇ (: 550, preferably at a temperature of ⁇ 20 ⁇ (: 020.
• the protective group (R 3 ) can be separated by a method known per se.
• Compound (VI) is represented by the general formula
• Compound (XI) is free carboxylic acid or compound (VI) This compound is subjected to the present reaction as a derivative similar to the above.
• This reaction is usually performed in an inert solvent. .
• Examples of the medium include water, acetone, dioxane, and acetonitrile.
• Organic solvents such as tril, black form, benzene, methylene chloride, chlorinated ethylene, tetrahydrofuran, ethyl acetate, N, N dimethylformamide, pyridine , And their mixtures
• the compound (H) is a reactive derivative thereof (eg, an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt, or a triethylaphthalate).
• Organic salts such as pyridine salts and pyridine salts).
• OMPI- In this reaction, it is preferable to carry out the reaction under cooling to avoid by-products of the isomer 2 —isomer, and a solvent that does not inhibit the reaction (eg, N, N -dimethylformamide, N, —dimethyl) Can easily proceed in the presence of thiacetoamide, hexamyl phosphoramide, aceton, acetonitril, dimethyl sulfoxide, cross-sectional form, methylene chloride). it can.
• a solvent that does not inhibit the reaction eg, N, N -dimethylformamide, N, —dimethyl
• the compound (x m) is subjected to this reaction as a free carboxylic acid or as a reactive derivative similar to that for the compound (VI).
• the compound (( ⁇ ) is .7 —amino-3 — (5 —methyl-1, -Thiadiazol-1 2 — i-Nore) Thiome Chinore-1 3-
• Compound (VI) is preferably a reactive derivative as described above.
• cephalosporin derivative (I) is pharmaceutically acceptable by conventional means.
• Acceptable acid addition salts such as mineral salts (eg, hydrochloride)
• cephalosporin derivative (I) thus produced is publicly available.
• the excipient is m
• starch for example, starch, anhydrous lactose, sugar, calcium carbonate, calcium phosphate
• the therapeutic agent for bacterial infection for oral administration may further include other ingredients.
• Additives such as binders (eg, starch,
• Lucellulose crystalline cellulose, etc.
• lubricants eg, stearyl
• a dosage form suitable for oral administration such as capsules, tablets, fine granules, granules, dry capsules and the like.
• B oc means t-butoxycarbonyl
• Example 7 (5 — methylone — 1, 3 — dioxonole 1 2 — on 1 4 — i-nore) methyl 7 1 [D — 0— (N-benzyloxycanolebonyl 1 L
• the carboxylate is dibenzylated with acetic monohydrobromic acid
• the insoluble material is removed by filtration and washed quickly with cold sodium bicarbonate solution and cold saline solution.
• the compound of Example 1 is obtained by adding 1 O ml.
• Boc—L—Alanine (2 g) is melted in anhydrous tetrahydrofuran (3 Q ml), and triethylamine (1.1 g) is added.
• Add the tanned solution to 10 ml of frans dropwise and stir at the same temperature for 30 minutes.
• 1.6 mg of D-mandelic acid and 50 mg of 4-dimethylaminopyridine and stir at 0 for 30 minutes and stir at room temperature for 2 hours.
• the solvent was distilled off under reduced pressure, and ethyl acetate was added to dissolve the residue.
• the residue was washed with water and brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. (Same compound as in Example 2) 830 mg is obtained. (Yield 24%)
• the filtrate was distilled off under reduced pressure, and the residue was treated with methanol.
• I R (nujol, cm); 3340, 1820, 1780, 1750, 1680

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Cephalosporin Compounds (AREA)

Priority Applications (5)

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• 1984
  • 1984-05-24 EP EP19840902068 patent/EP0186706A4/en not_active Withdrawn
  • 1984-05-24 WO PCT/JP1984/000267 patent/WO1985005360A1/ja not_active Ceased
  • 1984-05-24 FI FI860356A patent/FI860356L/fi not_active Application Discontinuation
• 1986
  • 1986-01-10 NO NO860072A patent/NO860072L/no unknown
  • 1986-01-17 DK DK22086A patent/DK22086A/da not_active Application Discontinuation

Non-Patent Citations (1)

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